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Gastric Cancer: the clinical significance of micrometastasis and tumor cell microinvolvement.

Romeo Giuli MD, resident.
School of General and Emergency Surgery.
University of Siena.   Italy.

June 2001.     Review Article.
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Gastric cancer patients diagnosed as free of lymph node metastasis by routine histologic examination after a curative resection may have recurrent disease.
It is possible that the tumor spreads in a different pattern from that indicated by the results of routine histopathologic examination, that generally samples about 1% of the submitted nodal tissue.
Studies applying serial step-sectioning, immunohistochemistry , or molecular assays have demonstrated small foci of metastatic cancer cells in regional nodes that previously were deemed free of metastases by routine histopathologic exam (Keene).

JR Siewert et al in a 1996 article affirms that the presence of three or more tumor cells in more than 10 per cent of the lymph nodes is of significant prognostic value in the pN0 cases. This is the case in which microinvolvement has an adverse impact on prognosis.
In fact the authors distinguish lymph nodes with deposits of tumor without a surrounding stromal reaction (microinvolvement) and true micrometastasis (tumor cells with a stromal reaction).
Therefore the frequent occurrence of microinvolvement is a strong argument favouring routine D2 lymph node dissection in surgery for gastric carcinoma in the early phase of lymph node metastasis (Siewert).

Natsugoe et others (Siewert's institute) in a 1998 article analyse a group of patients with esophageal squamous cell carcinoma and they riaffirm the distinction between micrometastases ( individual tumor cells or a cluster of tumor cells less than 0,5 mm in greatest dimension, with a stromal reaction) and tumor cell microinvolvement, TCM, (cluster of tumor cells or individual tumor cells without a stromal reaction).
MMs detected by IHC are present in a considerable proportion of esophageal SCC cases classified as pN0 by routine methods (31,7%) and these have a prognostic significance that justifies a reclassification of these cases as pN1.
For this finding it is recommended an extended lymphadenectomy for esophageal carcinoma and they deduce that ICH for cytokeratins in the lymph nodes of esophageal SCC is clinically useful ( Natsugoe).

Mueller and others (Siewert's institute) in a 2000 article, analyse MMs and TCM in the adenocarcinoma of the esophagogastric junction, a tumor that has risen more rapidly in incidence in Western industrialized countries than any other visceral malignancies.
This tumor has vague symptoms and most patients are first diagnosed when this carcinomas are locally advanced.
Therefore the only chance for a long term survival is a complete removal of the tumor. And because lymph nodes are frequent site of tumor recurrence it means that this compartment is an important site for occult tumor deposits.
In the AEG I tumor the rate of TCM alone is slightly higher (18% vs 10%), but not significantly so,than in patients with AEG II and AEG III tumors. On the other hand the rate of MMs is more than three times greater in patients with AEG II and AEG III tumors compared with patients with AEG I tumors (24% against 7%).
Moreover MMs in AEG II and AEG III have a negative prognostic impact that is similar to the finding of tumor cells by routine methods, whereas TCM alone has no such impact on patient prognosis.
Therefore an extensive lymphadenectomy may provide a prognostic benefit for patients with AEG II and AEG III tumors, even if they are classified as pN0 by routine histology. In contrast lymph node metastasis are rare in patients with adenocarcinomas of the distal esophagus that have no evidence of lymph node metastases by routine histologic methods. So patients with early ( pTI ) adenocarcinoma of the distal esophagus , which have a low likelihood of having regional lymph node metastasis , may undergo more limited forms of resection (Mueller).

The overall rate of occult lymph node metastases for patients with esophageal carcinoma in the Glickman's study is higher than the rate reported in the study by Mueller et al.(30,6% vs 16,7%), but the direct comparisons of these studies are very difficult due to differing detection methods and patient selection (a lower proportion of pT1 tumors in the Glickman's study). Moreover Glickman concludes that occult lymph node metastases is not an indipendent prognostic factor in esophageal adenocarcinoma or squamous cell carcinoma. And he does not recommend extensive lymph node sectioning with keratin immunostaining for prognostication of patients with these malignancies (Glickman).
Mueller recommends prospective studies to determine whether these newly detected cells represent an indipedent prognostic factor in patients with AEG II and III tumors (Mueller).
We can notice some different opinions between these cited conclusions and Natsugoe's study and Siewert's study, who affirms that multivariate analysis identifies microinvolvement as an indipendent prognostic factor (Siewert).

Ishida et al reports that gastric cancer patients with micrometastasis at Stage II have significantly worse prognosis than those without micrometastasis (Ishida).

Nakajo evaluates MMs and TCM in the lymph nodes of patients with T1 and T2 gastric cancer, and node negative by routine histologic examination. In this series of pN0 patients the incidence of MMs and/or TCM is 20,9% (Nakajo).
Single cells (TCM) cannot proliferate in the lymph node because they are killed by local and general immunocytes. Natural Killer cell infiltration is correlated positively with surgical outcome. The level of NK cells, when combined with lymphocitic infiltration, may be an indipendent prognostic factor for patients with gastric carcinoma (Ishigami).
On the other hand once tumor cells form a cluster (MM), these cells may easily proliferate and have matastatic potential.The prognosis of patients with MM was poorer than that of patients without MM (Nakajo).

Natsugoe reports the relationship between E cad expression in the primary tumor and the presence of MMs and/or TCM in esophageal carcinoma.
E cadherin is a member of the cadherin family and plays a role in regulating intercellular adhesion in epithelial tissues. Reduced E cad expression is closely associated with lymph node metastasis (Natsugoe).
Nakajo suggests that testing biopsy tumor specimens for E cad may aid in predicting the occurrence of MMs and/or TCM in T1 and T2 gastric cancers.
In patients who are preoperatively found to have reduced E cad expression extended lymphadenectomy should be performed (Nakajo).

With particular regard to T1 gastric cancer Cai intends to clarify the clinicopathologic characteristic of micrometastasis in lymph nodes and microinvasion in primary lesions for the treatment options of T1 gastric cancer ( in particular submucosal gastric cancer).
Survival analyses demonstrates a lesser 5 year survival in the patients with micrometastases in lymph nodes (82%) and with microinvasion to muscolaris propria (73%).
The incidence of nodal metastasis determined by immunohistochemical staining in the present study is of 34% (Cai).
Natsugoe et al performing a detailed reexamination of 3 serial sections of lymph nodes dissected from submucosal cancer, find a much higher incidence of nodal metastasis of 29,8% (Natsugoe).
Therefore in view of the high incidence of micrometastases in lymph nodes and microinvasion in primary lesions, at least a D2 lymphadenectomy, depending on the site of the lymph node involvement, is suggested at the time of surgery for patients with submucosal gastric cancer (Cai).
Kunisaki in fact reaffirms that it is difficult to suggest minimizing the dissection field in patients with submucosal cancer. However when the sites of lymph node metastasis are considered less invasive surgery is possible in each tumor site.
For example in the lower third of the stomach, distal gastrectomy with a D1 resection should be accompanied with dissection of the lymph nodes along the left gastric artery, anterosuperior common hepatic artery, celiac artery and proximal portion of the splenic artery (Kunisaki).
Cai describes that a high incidence of nodal involvement is found in submucosal cancers of large size (>2 cm; 43%), a depressed type (48%), lymphatic invasion (submucosal 3, 53%). A higher incidence of microinvasion is found with the diffuse-type carcinoma (33%) (Cai).

Maehara was one of the first medical doctors to highlight that even after curative resection of an early gastric cancer some patients die of recurrence, because they have occult micrometastasis in perigastric lymph nodes at the time of original diagnosis.
The presence of micrometastasis means a poorer prognosis, and metastatic lesions in the lymph nodes are more sensitive to anticancer drugs (Maehara).

Therefore we conclude that :

although the patients with MMs have an especially high risk for recurrence, randomised prospective study is needed to determine if this population actually benefits from postoperative adiuvant therapy (Nakajo);

the patients presenting with cytokeratin-positive cells in the lymph nodes must be closely monitored, and appropriate treatment must be tailored to each individual, (Maehara)

in patients who are preoperatively found to have reduced E cad expression extended lymphadenectomy should be performed (Nakajo),

immunohistochemical detection studies of occult lymph node metastases can be combined with studies about sentinel lymph node of gastric cancer.


S.A.Keene, MD and MJ Demeure, MD. The clinical significance of micrometastases and molecular metastases. Surgery volume 129, number 1; 1-5, 2001.

JR Siewert et al. Benefits of D2 lymph node dissection for patients with gastric cancer and pN0 and pN1 lymph node metastases. British Journal Surgery 1996, 83, 1144-47.

S. Natsugoe et al. Micrometastasis and tumor cell microinvolvement of lymph nodes from esopahageal squamous cell carcinoma. Cancer 1998; 83:858-66.

J.D. Mueller et al. Frequency and clinical impact of lymph node micrometastasis and tumor cell microinvolvement in patients with adenocarcinoma of the esophagogastric junction. Cancer 2000; 89:1874-82.

J.N. Glickman et al. The prognostic significance of lymph node metastases in patients with esophageal carcinoma. Cancer 1999; 85: 769-78.

Nakajo et al. Detection and prediction of micrometastasis in the lymph nodes of patients with pN0 gastric cancer. Annals of Surgical Oncology 2001, 8 (2) : 158-162.

S. Ishigami et al. Prognostic value of intramural natural killer cells in gastric carcinoma. Cancer 2000; 88: 577-83.

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J Cai et al. Micrometastasis in lymph nodes and microinvasion of the muscularis propria in primary lesions of submucosal gastric cancer. Surgery 1999: 126:32-9.

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Y Maehara et al. Clinical significance of occult micrometastasis in lymph nodes from patients with early gastric cancer who died of recurrence. Surgery 1996; 119: 397-402.

Van der Ven C. et al. Three field lymphadenectomy and pattern of lymph node spread in T3 adenocarcinoma of the distal esophagus and the gastro esophageal junction. Eur J Cardiothorac Surg 1999; 15: 769-73.

M. Miyata et al. Relationship between E-cadherin expression and lymph node metastases in human esophageal cancer. Int J Oncol 1994; 4: 61-5.

KK. Krishnadath et al. Reduced expression of the cadherin-catenin complex in oesophageal adenocarcinoma correlates with poor prognosis. J Pathol 1997; 182: 331-8.

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